3-Aryloxy-8-aza-bicyclo[3.2.1]]oct-6-ene derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

ABSTRACT

This invention relates to novel 8-aza-bicyclo[3.2.1]oct-6-ene derivatives useful as monoamine neurotransmitter re-uptake inhibitors. 
     In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL FIELD

This invention relates to novel 8-aza-bicyclo[3.2.1]oct-6-enederivatives useful as monoamine neurotransmitter re-uptake inhibitors.

In other aspects the invention relates to the use of these compounds ina method for therapy and to pharmaceutical compositions comprising thecompounds of the invention.

BACKGROUND ART

Serotonin Selective Reuptake Inhibitors (SSRIs) currently provideefficacy in the treatment of several CNS disorders, including depressionand panic disorder. SSRIs are generally perceived by psychiatrists andprimary care physicians as effective, well-tolerated and easilyadministered. However, they are associated with a number of undesirablefeatures.

Thus, there is still a strong need for compounds with an optimisedpharmacological profile as regards the activity on reuptake of themonoamine neurotransmitters serotonin, dopamine and noradrenaline, suchas the ratio of the serotonin reuptake versus the noradrenaline anddopamine reuptake activity.

SUMMARY OF THE INVENTION

In its first aspect, the invention provides a compound of Formula I:

any of its isomers or any mixture of its isomers, or a pharmaceuticallyacceptable salt thereof,wherein R^(a) and R^(b) are as defined below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof the invention, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.

In a further aspect, the invention provides the use of a compound of theinvention, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In a still further aspect, the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a compound of theinvention, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

Substituted 8-aza-bicyclo[3.2.1]oct-6-ene Derivatives

In its first aspect the present invention provides compounds of formulaI

any of its isomers or any mixture of its isomers,or a pharmaceutically acceptable salt thereof;whereinR^(a) represents hydrogen or alkyl;

-   -   which alkyl is optionally substituted with one or more        substituents independently selected from the group consisting        of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy,            amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl and alkynyl; and            R^(b) represents an aryl group;    -   which aryl group is optionally substituted with one or more        substituents independently selected from the group consisting        of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, nitro,            hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl,            methylenedioxy, ethylenedioxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, alkynyl, —NR′R″, —(C═O)NR′R″ or            —NR′(C═O)R″;            -   wherein R′ and R″ independent of each other are hydrogen                or alkyl.

In one embodiment, R^(a) represents hydrogen or alkyl. In a specialembodiment, R^(a) represents hydrogen. In a further embodiment, R^(a)represents alkyl, such as methyl.

In a still further embodiment, R^(b) represents a phenyl group, whichphenyl group is optionally substituted with one or more substituentsindependently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano and alkoxy.

In a further embodiment, R^(b) represents a phenyl group, which phenylgroup is substituted twice with substituents independently selected fromthe group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyanoand alkoxy.

In a still further embodiment, R^(b) represents a naphthyl group, whichnaphthyl group is optionally substituted with one or more substituentsindependently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano and alkoxy.

In a special embodiment, R^(b) represents a dihalophenyl, such asdichlorophenyl, such as 3,4-dichlorophenyl. In a further embodiment,R^(b) represents a bromo-chlorophenyl, such as 3-bromo-4-chloro-phenylor 4-bromo-3-chloro-phenyl. In a still further embodiment, R^(b)represents a chloro-fluoro-phenyl, such as 3-chloro-4-fluoro-phenyl or4-chloro-3-fluoro-phenyl.

In a further special embodiment, R^(b) represents an alkoxy-naphthyl,such as methoxy-naphthyl, such as 6-methoxy-naphthalen-2-yl.

In a special embodiment the compound of the invention is

-   exo-3-(3,4-Dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;    exo-3-(3-Bromo-4-chloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(3-Chloro-4-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(4-Bromo-3-chloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(4-Chloro-3-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(3,4-Dichloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(3-Bromo-4-chloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(3-Chloro-4-fluoro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(4-Bromo-3-chloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;-   exo-3-(4-Chloro-3-fluoro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;    or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromoor iodo.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contains of from one to six carbon atoms (C₁₋₆-alkyl),including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl andisohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkyl group,including butyl, isobutyl, secondary butyl, and tertiary butyl. Inanother preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexadienyl, or 1,3,5-hexatrienyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butadiynyl; 1-, 2-, 3-, 4-pentynyl, or1,3-pentadiynyl; 1-, 2-, 3-, 4-, or 5-hexynyl, or 1,3-hexadiynyl or1,3,5-hexatriynyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

In the context of this invention an aryl group designates a carbocyclicaromatic ring system such as phenyl, naphthyl (1-naphthyl or 2-naphthyl)or fluorenyl.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydro-chloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a chemicalcompound of the invention include, without limitation, the sodium, thepotassium, the calcium, the magnesium, the zinc, the aluminium, thelithium, the choline, the lysinium, and the ammonium salt, and the like,of a chemical compound of the invention containing an anionic group.Such cationic salts may be formed by procedures well known and describedin the art.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention include compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may exist in different stereoisomericforms—including enantiomers, diastereomers and cis-trans-isomers.

The invention includes all such isomers and any mixtures thereofincluding racemic mixtures.

Moreover, the substituent —O—R^(b) on position 3 of the8-aza-bicyclo[3.2.1]oct-6-ene skeleton of formula I may in particular bein the exo or endo configuration. In one embodiment of the invention thesubstituent at position 3 is in the exo configuration. In anotherembodiment of the invention the substituent at position 3 is in the endoconfiguration.

The invention includes all such isomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the enantiomeric compounds(including enantiomeric intermediates) is—in the case the compound beinga chiral acid—by use of an optically active amine, and liberating thediastereomeric, resolved salt by treatment with an acid. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of D- or L- (tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials or intermediates.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention the labelled compoundhas one or more atoms replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. The labelling will allow easy quantitative detection of saidcompound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradio-nuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

Compounds of the invention may be tested for their ability to inhibitreuptake of the monoamines dopamine, noradrenaline and serotonin insynaptosomes e.g. such as described in WO 97/30997. Based on thebalanced activity observed in these tests the compound of the inventionis considered useful for the treatment, prevention or alleviation of adisease or a disorder or a condition of a mammal, including a human,which disease, disorder or condition is responsive to inhibition ofmonoamine neurotransmitter re-uptake in the central nervous system.

In a special embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of: mood disorder,depression, atypical depression, depression secondary to pain, majordepressive disorder, dysthymic disorder, bipolar disorder, bipolar Idisorder, bipolar II disorder, cyclothymic disorder, mood disorder dueto a general medical condition, substance-induced mood disorder,pseudodementia, Ganser's syndrome, obsessive compulsive disorder, panicdisorder, panic disorder without agoraphobia, panic disorder withagoraphobia, agoraphobia without history of panic disorder, panicattack, memory deficits, memory loss, attention deficit hyperactivitydisorder, obesity, anxiety, generalized anxiety disorder, eatingdisorder, Parkinson's disease, parkinsonism, dementia, dementia ofageing, senile dementia, Alzheimer's disease, acquired immunodeficiencysyndrome dementia complex, memory dysfunction in ageing, specificphobia, social phobia, social anxiety disorder, post-traumatic stressdisorder, acute stress disorder, drug addiction, drug abuse, cocaineabuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism,kleptomania, pain, chronic pain, inflammatory pain, neuropathic pain,migraine pain, tension-type headache, chronic tension-type headache,pain associated with depression, fibromyalgia, arthritis,osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritablebowel pain, irritable bowel syndrome, post-operative pain,post-mastectomy pain syndrome (PMPS), post-stroke pain, drug-inducedneuropathy, diabetic neuropathy, sympathetically-maintained pain,trigeminal neuralgia, dental pain, myofacial pain, phantom-limb pain,bulimia, premenstrual syndrome, premenstrual dysphoric disorder, lateluteal phase syndrome, post-traumatic syndrome, chronic fatiguesyndrome, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities. Ina preferred embodiment, the compounds are considered useful for thetreatment, prevention or alleviation of depression.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Preferred compounds of the invention show a biological activity in thesub-micromolar and micromolar range, i.e. of from below 1 to about 100μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers, and, optionally, othertherapeutic and/or prophylactic ingredients, known and used in the art.The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not harmful to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral-use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to inhibition of monoamine neurotransmitterre-uptake in the central nervous system, and which method comprisesadministering to such a living animal body, including a human, in needthereof an effective amount of a chemical compound of the invention.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

General: All reactions involving air sensitive reagents or intermediateswere performed under nitrogen and in anhydrous solvents. Magnesiumsulphate was used as drying agent in the workup-procedures and solventswere evaporated under reduced pressure.

Method A exo-3-(3,4-Dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

2,2,2-Trichloroethyl chloroformate (2.99 g, 14.1 mmol) was added to amixture of3-(3,4-dichloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene (1.34 g,4.7 mmol) and toluene (25 ml). The mixture was stirred for 30 minfollowed by 15 h at 100° C. Water (50 ml) was added and the organicphase was separated and was washed with water (2×25 ml). The crudemixture obtained by evaporation was solved in acetic acid (40 ml) andwater (10 ml). Zinc powder (2.0 g) was added to the mixture in portionsfollowed by stirring for 5 h. Ice-water (50 ml) was added followed byconcentrated aqueous ammonia (50 ml). The mixture was extracted withdichloromethane (2×50 ml). The hydrochloric acid salt was precipitatedby adding hydrochloric acid solved in ethanol to the free base solved indiethylether. Yield 0.84 g (58%). Mp 200° C. (decomp.).

exo-3-(3-Bromo-4-chloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method A. Mp 240-243° C. LC-ESI-HRMS of [M+H]+shows 313.9952 Da. Calc. 313.99473 Da, dev. 1.5 ppm.

exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method A. LC-ESI-HRMS of [M+H]+ shows 282.1501Da. Calc. 282.149404 Da, dev. 2.5 ppm.

exo-3-(3-Chloro-4-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method A. Mp 216-219° C. LC-ESI-HRMS of [M+H]+shows 254.0737 Da. Calc. 254.074795 Da, dev. −4.3 ppm.

exo-3-(4-Bromo-3-chloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method A. LC-ESI-HRMS of [M+H]+ shows 313.995Da. Calc. 313.99473 Da, dev. 0.9 ppm.

exo-3-(4-Chloro-3-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method A. LC-ESI-HRMS of [M+H]+ shows 254.0749Da. Calc. 254.074795 Da, dev. 0.4 ppm.

Method Bexo-3-(3,4-Dichloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

A mixture of diethylazodicarboxylate (4.0 g, 23 mmol) in dioxane (10 ml)was added to triphenylphosphine (6.03 g, 23 mmol), solved in dioxane (40ml) at room temperature. The mixture was stirred for 15 min.endo-8-Methyl-8-aza-bicyclo[3.2.1]oct-6-ene-3-ol (3.3 g, 19 mmol) solvedin dioxane (10 ml) was added to the mixture followed by3,4-dichlorophenol (3.3 g, 20 mmol). The temperature raised to 30° C.due to an exothermic reaction. The mixture was stirred at roomtemperature overnight. Water (100 ml) and aqueous hydrochloric acid (15ml, 4 M) was added and was washed with diethylether (3×50 ml). Theaqueous phase was made alkaline by adding sodium hydroxide (20 ml, 4 M)followed by extraction with diethylether (3×80 ml). The crude mixturewas purified by silica gel column chromatography using dichloromethanefollowed by a mixture of methanol and dichloromethane and aqueousammonia (40:9:1). The hydrochloric acid salt was prepared by adding amixture of hydrochloric acid solved in ethanol. Yield 2.52 g (41%). Mp248.8° C.

exo-3-(3-Bromo-4-chloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method B. Mp 234-236° C. LC-ESI-HRMS of [M+H]+shows 328.0098 Da. Calc. 328.01038 Da, dev. −1.8 ppm.

exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-enefree base

Was prepared according to method B. Mp 240° C. (dec.) LC-ESI-HRMS of[M+H]+ shows 296.1639 Da. Calc. 296.165054 Da, dev. −3.9 ppm.

exo-3-(3-Chloro-4-fluoro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method B. Mp 200-203° C. LC-ESI-HRMS of [M+H]+shows 268.0891 Da. Calc. 268.090445 Da, dev. −5 ppm.

exo-3-(4-Bromo-3-chloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-enefree base

Was prepared according to method B. LC-ESI-HRMS of [M+H]+ shows 328.0092Da. Calc. 328.01038 Da, dev. −3.6 ppm.

exo-3-(4-Chloro-3-fluoro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-enehydrochloric acid salt

Was prepared according to method B. LC-ESI-HRMS of [M+H]+ shows 268.0915Da. Calc. 268.090445 Da, dev. 3.9 ppm.

Method C endo-8-Methyl-8-aza-bicyclo[3.2.1]oct-6-ene-3-ol (intermediate)

A mixture of zinc powder (10 g) and hydrochloric acid (10 ml, 1 M) wasstirred for 1 minute and washed with hydrochloric acid (3×10 ml, 1 M)and water (5×10 ml) followed by aqueous cupper sulphate (25 ml, 2%),water (5×10 ml), ethanol (10 ml, 96%) and diethylether (10 ml) followedby drying. The title compound was prepared from scopolamine hydrobromidetrihydrate and zinc powder followed by hydrolysis by treatment withaqueous sodium hydroxide according to Tetrahedron Letters 42 (2001), p1975.

Test Example In Vitro Inhibition Activity

A number of compounds were tested for their ability to inhibit thereuptake of the monoamine neurotransmitters dopamine (DA) noradrenaline(NA) and serotonine (5-HT) in synaptosomes as described in WO 97/16451.

The test values are given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-DA, ³H-NA, or³H-5-HT by 50%).

Test results obtained by testing selected compounds of the presentinvention appear from the below table:

TABLE 1 DA-uptake NA-uptake 5-HT-uptake Test compound IC₅₀(μM) IC₅₀(μM)IC₅₀(μM) 1^(st) compound of method A; 0.22 0.027 0.0025exo-3-(3,4-Dichloro-phenoxy)-8-aza- bicyclo[3.2.1]oct-6-ene 2^(nd)compound of method A; 0.17 0.11 0.021exo-3-(3-Bromo-4-chloro-phenoxy)-8- aza-bicyclo[3.2.1]oct-6-ene 3^(rd)compound of method B; 0.11 0.17 0.48exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene

1-11. (canceled)
 12. A compound of Formula I:

any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof; wherein R^(a) representshydrogen or alkyl; which alkyl is optionally substituted with one ormore substituents independently selected from the group consisting of:halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro,alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl andalkynyl; and R^(b) represents an aryl group; which aryl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of: halo, trifluoromethyl,trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy,alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, —NR′R″, —(C═O)NR′R″ or—NR′(C═O)R″; wherein R′ and R″ independent of each other are hydrogen oralkyl.
 13. The compound of claim 12, or a pharmaceutically acceptablesalt thereof, wherein R^(a) represents hydrogen or alkyl.
 14. Thecompound of claim 12, or a pharmaceutically acceptable salt thereof,wherein R^(b) represents a phenyl group, which phenyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of: halo, trifluoromethyl,trifluoromethoxy, cyano and alkoxy.
 15. The compound of claim 12, or apharmaceutically acceptable salt thereof, wherein R^(b) represents aphenyl group, which phenyl group is substituted twice with substituentsindependently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano and alkoxy.
 16. The compound ofclaim 12, or a pharmaceutically acceptable salt thereof, wherein R^(b)represents a naphthyl group, which naphthyl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyanoand alkoxy.
 17. The compound of claim 12, which isexo-3-(3,4-Dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(3-Bromo-4-chloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(3-Chloro-4-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(4-Bromo-3-chloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(4-Chloro-3-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(3,4-Dichloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(3-Bromo-4-chloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(3-Chloro-4-fluoro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(4-Bromo-3-chloro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;exo-3-(4-Chloro-3-fluoro-phenoxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-6-ene;or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof claim 12, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.
 19. A methodfor treatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a compound according toclaim 12, any of its stereoisomers or any mixture of its stereoisomers,or a pharmaceutically acceptable salt thereof.
 20. The method accordingto claim 19, wherein the disease, disorder or condition is mooddisorder, depression, atypical depression, depression secondary to pain,major depressive disorder, dysthymic disorder, bipolar disorder, bipolarI disorder, bipolar II disorder, cyclothymic disorder, mood disorder dueto a general medical condition, substance-induced mood disorder,pseudodementia, Ganser's syndrome, obsessive compulsive disorder, panicdisorder, panic disorder without agoraphobia, panic disorder withagoraphobia, agoraphobia without history of panic disorder, panicattack, memory deficits, memory loss, attention deficit hyperactivitydisorder, obesity, anxiety, generalized anxiety disorder, eatingdisorder, Parkinson's disease, parkinsonism, dementia, dementia ofageing, senile dementia, Alzheimer's disease, acquired immunodeficiencysyndrome dementia complex, memory dysfunction in ageing, specificphobia, social phobia, social anxiety disorder, post-traumatic stressdisorder, acute stress disorder, drug addiction, drug abuse, cocaineabuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism,kleptomania, pain, chronic pain, inflammatory pain, neuropathic pain,migraine pain, tension-type headache, chronic tension-type headache,pain associated with depression, fibromyalgia, arthritis,osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritablebowel pain, irritable bowel syndrome, post-operative pain,post-mastectomy pain syndrome (PMPS), post-stroke pain, drug-inducedneuropathy, diabetic neuropathy, sympathetically-maintained pain,trigeminal neuralgia, dental pain, myofacial pain, phantom-limb pain,bulimia, premenstrual syndrome, premenstrual dysphoric disorder, lateluteal phase syndrome, post-traumatic syndrome, chronic fatiguesyndrome, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities.